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This invention is directed to compositions and methods for treating anorectal disorders such as anal fissures, anal ulcer, hemorrhoidal diseases and levator spasm by administering to an appropriate anal area (for example, the internal anal canal) of a subject in need of such treatment an agent or combination of agents which relaxes the internal anal sphincter muscle. More specifically, this invention describes compositions and methods for treating anorectal disorders with agents which induce an increase in cyclic nucleotides in the anal sphincter muscle or which mimic the actions of cyclic nucleotides or reduce intracellular calcium concentrations in the affected anal sphincter muscle tissue, thereby reducing anal sphincter hypertonicity and/or spasm in patients afflicted with such disorders.
In general, anal fissure (fissure-in-ano), anal ulcer, hemorrhoidal diseases, and levator spasm (proctalgia fugax) are relatively common benign conditions of the anorectal area which affect subjects, including humans, of all ages, races, and sexes. While hemorrhoids and anal fissures do not garner the attention given to life threatening diseases, they are responsible for considerable suffering and disability, affecting over 26 million people in the U.S., Europe, and Japan.
An anal fissure or ulcer is a tear or ulcer of the mucosa or lining tissue of the distal anal canal. An anal fissure or ulcer can be associated with another systemic or local disease, but is more frequently present as an isolated finding. The typical idiopathic fissure or ulcer is confined to the anal mucosa and usually lies in the posterior midline, distal to the dentate line. An individual with an anal fissure or ulcer frequently experiences anal pain and bleeding, the pain being more pronounced during and after bowel movements.
Hemorrhoids are specialized vascular areas lying subjacent to the anal mucosa. Symptomatic hemorrhoidal diseases are manifested by bleeding, thrombosis and/or prolapse of the hemorrhoidal tissues. Commonly, internal hemorrhoidal tissue bulges into the anal canal during defecation and results in bleeding and pain. As the tissue enlarges, further bleeding, pain, prolapse and thrombosis can ensue. The thrombosis of hemorrhoids is yet another cause of bleeding and pain.
Levator spasm is a condition affecting women more frequently than men. This syndrome is characterized by spasm of the levator ani muscle, a portion of the anal sphincter complex. The patient suffering from levator spasm may experience severe, episodic rectal pain. A physical exam may reveal spasm of the puborectalis muscle and pain may be reproduced by direct pressure on this muscle. Bleeding is normally not associated with this condition.
Hemorrhoids are the most prevalent anorectal disorder and are the most common cause of hematochezia (i.e., passage of bloody stools). Hemorrhoidal disease is the consequence of distal displacement of the anal cushions, which normally play an important role in continence. The causes of hemorrhoids are not known. The most consistently demonstrated physiological abnormality is increased resting anal pressure (Hancock B. D., Br J Surg 64(2):92-5 (1975); Loder, P. B., Br J Surg 81(7):946-54 (1994)). Patients with non-prolapsing hemorrhoids appear to have higher anal pressures than those with prolapsing hemorrhoids (Arabi, Y. et al., Am J Surg 134(5):608-10 (1977); Sun, W. M. et al., Br J Surg 77(4): 458-62, (1990)), although the therapeutic implications of this observation remain unclear. Treatment is dependent on the degree of hemorrhoid prolapse and symptoms. Most cases (first- and second-degree hemorrhoids) generally respond to conservative medical treatment (e.g., dietary changes, sitz baths) or non-surgical procedures (e.g., rubber band ligation). Acutely thrombosed external hemorrhoids are usually characterized by severe anal pain, and internal anal sphincter hypertonia may play a role in the etiology of this pain (Gorfine, S. R., Dis Colon Rectum 38(5): 453-7 (1995)). Surgical excision of symptomatic thrombosed external hemorrhoids is indicated within 48 to 72 hours of the onset of pain. Post-hemorrhoidectomy pain is severe, disproportionate to the surgery itself, and requires the use of narcotic analgesics, which unfortunately complicate recovery by causing constipation. Anal dilatation and lateral internal sphincterotomy as treatments to reduce anal sphincter pressure in hemorrhoids have been used successfully, both as stand alone procedures and in conjunction with hemorrhoidectomy (Keighley, M. R. et al., Br Med J J2(6196):967-9 (1979); Schouten W. R. et al., Dis Colon Rectum 28(12), 869-72 (1986); Galizia et al., Eur J Surg 166(3):223-8 (2000)).
Others have reported that the addition of lateral internal sphincterotomy to routine hemorrhoidectomy is unnecessary and carries the added risk of incontinence (Mathai, V. et al., Br J Surg. 83(3):380-2 (1996)).
Anal fissure is one of the most common causes of anorectal pain. Anal fissures are tears in the mucosa of the distal anal canal, usually along the posterior midline. The exact causes of anal fissures remain unknown. They are often associated with trauma, e.g., passage of a hard stool, but can also occur during bouts of diarrhea, childbirth, or ulceration of a hemorrhoid (Lund, J. N. et al., Br J Surg. 83(10): 1335-44 (1996)). The most common symptom is pain at defecation, which can be quite severe and last for a variable time afterwards. The pain is chiefly due to an intense spasm of the internal anal sphincter muscle. Most anal fissures are adequately treated with sitz baths, stool softeners, and analgesics. Approximately 60% of acute anal fissures will heal within three weeks using this treatment regimen. Acute anal fissures, which do not heal, become chronic anal fissures or anal ulcers. Hypertonicity of the internal anal sphincter muscle and mucosal ischemia are thought to play an important role in the pathogenesis of chronic anal fissures (Schouten W. R. et al., Dis Colon Rectum 37(7):664-9 (1994); Lund, J. N. et al., Br J Surg 83(10): 1335-44 (1996)). Anodermal blood flow at the posterior midline is less than other regions of the anal canal, and perfusion of the posterior mucosa is inversely related to anal pressure. Chronic anal fissures are typically not responsive to conservative medical therapy. Current treatments are therefore directed at relieving sphincter spasm, and include anal dilatation (under anesthesia), or more commonly, lateral sphincterotomy of the internal anal sphincter. Healing occurs following surgical sphincterotomy in 95% of cases. Successful sphincterotomy (or anal dilatation) is associated with a significant decrease in intra-anal pressure and increase in anodermal blood flow (Lund, J. N. et al., Br J Surg 83(10): 1335-44, (1996); Schouten W. R. et al., Scan J Gastroenterol. Suppl 218: 78-81 (1996)). However, up to 35% of patients may experience some form of incontinence following the surgical procedure (Sharp, F. R., Am J Surg 171(5):512-5 (1996)). Incontinence of stool and flatulence is a humiliating disability with numerous social, medical, and financial implications. There is clearly a large unmet medical need to develop effective, non-surgical treatments for anal fissure and other colorectal conditions, including acute hemorrhoidal disease, hemorrhoidectomy pain, proctalgia fugax, and severe constipation. Considerable recent progress has been made in the understanding of anorectal physiology and pharmacology. These new insights provide important implications and opportunities for the pharmacological management of colorectal disorders.
Sphincters are circular groups of smooth muscle that control the orifices of hollow organs. They are present throughout the gastrointestinal tract and control the passage of materials through this system of the body. When constricted, sphincters close orifices leading to or from the hollow organs, such as the stomach, intestine, rectum, etc. In order for the orifice to open, the sphincter must relax. The, sphincter that closes the anus (sphincter ani) consists of two sphincter muscle groups. The external anal sphincter is a thin flat plane of striated muscle fibers adherent to the integument surrounding the margin of the anus. It is innervated by motor neurons and is under voluntary control. The internal anal sphincter (IAS) is a ring of smooth muscle that surrounds the anal canal and is formed by a specialized aggregation of involuntary circular smooth muscle fibers of the intestine. The IAS is largely responsible for resting anal sphincter pressure and continence which is maintained by intrinsic myogenic tone and regulated by both intrinsic and extrinsic innervation from the autonomic nervous system (Penninckx, F. et al., Baillieres Clin Gastroenterol 6(1)193-214 (1992); Speakman, C. T. Eur J Gastroenterol Hepatol 9(5):442-6 (1997)).
The IAS smooth muscle constantly generates rhythmic electrical slow waves, but no action potentials. The slow waves are linked to calcium fluxes via voltage-dependent, L-type calcium channels that are responsible for mechanical force generation and contraction of the sphincter. Accordingly, several calcium channel antagonists, including diltiazem and nifedipine, have been documented to reduce anal pressure in man (Jonard et al., Lancet 1(8535): 754 (1987); Chrysos, E. et al., Dis Colon Rectum 39(2): 212-6 (1996); Antropoli, C. et al., Dis Colon Rectum 42(8):1011-5 (1999); Carapeti, E. A. et al., Gut 45(5) 719-722 (1999); Carapeti, E. A. et al., Br J Surg 86(2):267-70 (1999), and in several reports, to heal chronic anal fissures (Cook, T. A. et al., Br J Surg 86(10):1269-73 (1999); Brisinda, G. et al., Br J Surg 87(2): 251 (2000)).
Sympathetic innervation of the IAS, supplied by the hypogastric nerves, is primarily excitatory and functions to enhance myogenic tone through the action of norepinephrine on smooth muscle xcex11-adrenergic receptors (Frenckner, B., et al., Gut 17(4):306-12 (1976); Speakman, C. T. et al., Dig Dis Sci 38(11)1961-9 (1993)). The xcex11-adrenergic receptor antagonists phentolamine and indoramin reduce anal canal pressure when administered to healthy volunteers or patients with chronic anal fissures (Speakman, C. T., Eur J. Gastroenterology 9(5):442-6 (1997); Pitt, J. et al., Dis Colon Rectum 43(6)800-803 (2000)). Conversely, the xcex1-receptor agonists methoxamine and phenylephrine increase anal pressure (Speakman, C. T. 1997 supra; Carapeti, E. A. et al., Br J Surg 86(2):267-70 (1999)). Low anal pressure is associated with incontinence (Speakman, C. T. Gastroenterology 9(5):442-6 (1997)). Speakman, C. T. et al., (Speakman, C. T. et al., Dig. Dis Sci. 38(11):1961-9 (1993)) reported that the IAS of incontinent patients exhibit reduced sensitivity to norepinephrine. Although the xcex1-adrenergic receptor population is dominant, xcex2-adrenergic receptors are also present on human IAS, and mediate relaxation (Parks, A. G., et al., Gut 10(8):674-7 (1969); Burleigh, D. E., et al., Gastroenterology 77(3): 484-90, (1979). The contractile response of the IAS to norepinephrine can be converted to relaxation in the presence of selective xcex1-receptor blockade, both in vitro and in normal human volunteers (Burleigh, D. E., et al., Gastroenterology 77(3): 484-90, (1979); Speakman, C. T., Eur J Gastroenterology 9(5):442-6 (1997)). Regadas and colleagues (Regadas, F. S. et al., Br J Surg 80(6):799-801 (1993)) demonstrated that isolated IAS strips from chronic anal fissure patients were significantly more sensitive to the relaxant effects of the xcex2-adrenergic agonist isoproterenol than control tissues, whereas no differences were noted in the contractile responses to phenylephrine and potassium chloride (a membrane depolarizing agent). However, it remains to be determined whether xcex2-adrenergic agonists offer disease-specific advantages for the treatment of chronic anal fissure.
The IAS relaxes in response to rectal distention (the rectoanal inhibitory reflex). The nerves mediating the rectoanal inhibitory reflex lie entirely within the wall of the gut (enteric inhibitory neurons), and descend from the rectum to the IAS. Electrical field stimulation (EFS) mimics the effects of intrinsic nerve stimulation on isolated smooth muscle strips. IAS strips are relaxed by EFS, an effect that is abolished by the neurotoxin tetrodotoxin, but is unaffected by antagonists of the classical neurotransmitters, acetylcholine or norepinephrine. The inhibitory nerves are thus classified as non-adrenergic, non-cholinergic (NANC) nerves. Adenosine triphosphate (ATP) and vasoactive intestinal peptide (VIP) were first suggested as NANC neurotransmitter candidates since they mimicked the relaxation elicited by electrical stimulation of motor nerve fibers (Burnstock, G. et al., Br J Pharmacol. 46(2):234-42 (1972); Bitar, K. N. et al., Science 216(4545): 531-3 (1982)). However, ATP and VIP, either separately or together, could not account for all inhibitory neurotransmission in gastrointestinal smooth muscle, and their roles have not been established in man (Burleigh, D. E. et al., Gastroenterology 77(3): 484-90 (1979); Burleigh, D. E., J Pharm Pharmacol 35(4):258-60 (1983); Brookes, S. J., J Gastroenterol Hepatol 8(6):590-603 (1993).
Recent studies indicate that NO plays an important role in NANC nerve mediated relaxation of the IAS. In an animal model, Rattan, S. et al., (Rattan, S. et al., Am J Physiol 262 (1 Pt 1):G107-12 (1992) demonstrated that IAS relaxation associated with the rectoanal reflex (induced by rectal balloon distention), or neural stimulation, was blocked by inhibition of NO synthase (NOS) with L-NNA [N5-(nitroamidino)-L-2,5-diaminopentanoic acid], but not with D-NNA. Block of the rectoanal reflex by L-NNR was reversed by L-arginine in a stereospecific manner, implicating NO or NO-like substances as mediators of NANC nerve mediated IAS relaxation. NO was shown to directly relax the IAS in a concentration-dependent manner in vitro, mimicking the effect of NANC nerve stimulation by EFS. NANC nerve-mediated relaxation of IAS strips in vitro was blocked by inhibition of NO synthase with L-NNA, and the block was reversed by L-arginine, but not D-arginine (Rattan, S. et al., Am J Physiol 262 (1 Pt 1):G107-12, (1992) and Rattan, S. et al., Gastroenterology 103(1):43-50 (1992)). Similar observations have been made using isolated muscle strips of human IAS (Burleigh Gastroenterology 102(2): 679-83 (1992); O""Kelly, T. J. et al., Br J Surg 80(10): 1337-41, (1993)). The direct release of NO following NANC nerve stimulation of opossum IAS strips was demonstrated using a specific chemiluminescence detection method (Chakder, S. et al., Am J Physiol., 264 (4 Pt 1)G702-7 (1993)). O""Kelly (O""Kelly, T. J. et al., Dis Colon Rectum 37(4): 35-7 (1994)) recently demonstrated the presence of NOS in neurons of the myenteric plexus that project throughout the IAS and lay in close proximity to smooth muscle cells. In Hirschsprung""s disease, a condition in which the rectoanal reflex is absent, NOS containing nerves were absent from the non-relaxing segment, but present in the normal segment of the gut (O""Kelly, T. J. et al., J Pediatric Surgery 29(2): 294-9 (1994)). These observations fulfill most of the criteria for NO as an inhibitory mediator or neurotransmitter.
A number of potent vasodilators and smooth muscle relaxants are known to chemically release NO on or within target cells, and thus are known as NO donors. Some NO donors, e.g., nitroglycerin, are widely used therapeutically as coronary vasodilators to treat heart disease. In keeping with the role of NO as an inhibitory neurotransmitter mediating relaxation of the IAS, NO donors are beginning to be explored clinically as drugs to treat anal disorders associated with IAS hypertonicity. Significantly, nitroglycerin (Gorfine, S. R., Dis Colon Rectum, 38(5):453-6 (1995); Watson, S. J. et al., Br J Surgery 83(6):771-5, 1996; Lund, J. N. et al., Lancet 349: 9044 (1997)) and isosorbide dinitrate have been used to effect a reversible chemical sphincterotomy in patients with chronic anal fissure. These drugs reduce maximal resting anal pressure and, improve anodermal blood flow, reduce pain, and heal fissures in a majority of the patients. Nitroglycerin has also been shown to reduce the throbbing pain of acute hemorrhoidal thrombosis and proctalgia fugax (Gorfine, S. R., Dis Colon Rectum 38(5):453-6 (1995); Lowenstein, B. et al., Dis Colon Rectum 41(5):667-8 (1998)).
U.S. Pat. Nos. 5,504,117 and 5,693,676 describe the use of NO donors for the treatment of anorectal conditions. However, the development of adverse side effects such as the development of headaches has limited the use of NO donors in stand alone therapy, especially at higher doses.
One problem associated with topical nitroglycerin therapy, which may limit its effectiveness, is the incidence of headache, particularly at higher doses (Palazzo, F. F. et al., J R Coll Surg Edinb 45(3):168-70 (2000)). The headache is presumably due to systemic effects of nitroglycerin and is generally transient, but can affect patient compliance. There is a need for treatment methods strategies which enhance the local effect of nitroglycerin and minimize its systemic side effects. A second potential problem of nitrates is the development of drug tolerance, a problem well documented for nitrate therapy in cardiovascular disease (Fung, H. L., et al., Cardiovasc Drugs Ther 8(3):489-99, (1994)). Tolerance, if present, would limit the ability of nitroglycerin to produce a sustained relaxation of the IAS, which may be necessary for healing particularly refractant chronic anal fissures.
There is clearly a significant need for other non-surgical treatments of anorectal disorders, including, for example, anal fissures and other anorectal conditions caused by anal sphincter spasm and or hypertonicity, including acute hemorrhoidal diseases and proctalgia fugax.
There is thus a need for alternative methods and compositions for reducing anal sphincter pressure that complement or supplant nitroglycerin.
The use of a topical or intra-rectal pharmaceutical preparation that complements or supplants nitroglycerin for the treatment of chronic anal fissures and other anorectal disorders can provide the first effective alternative to surgery for this painful disorder.
In one aspect, the present invention provides compositions for the treatment of anorectal disorders comprising a nitric oxide donor in combination with a second agent (typically one which modulates levels of cAMP or cGMP). The second agent can be a phosphodiesterase type V (PDE V) inhibitor, a phosphodiesterase type II (PDE II) inhibitor, a phosphodiesterase type IV (PDE IV) inhibitor, a nonspecific PDE inhibitor, a xcex2-adrenergic agonist, a cAMP-dependent protein kinase activator, an estrogen or estrogen-like compound, or an xcex11-adrenergic antagonist. The agent can also be a superoxide anion (O2xe2x88x92) scavenger, an ATP-sensitive K+ channel activator, a sympathetic nerve terminal destroyer, or a smooth muscle relaxant, although these agents do not directly modulate either cAMP or cGMP levels. The present invention further provides methods of using these compositions.
In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising a phosphodiesterase inhibitor, preferably a PDE II inhibitor, a PDE IV inhibitor or a PDE V inhibitor, either alone or in combination with another agent selected from xcex2-adrenergic receptor agonists, xcex11-adrenergic antagonists, estrogens, L-type Ca2+ channel blockers, ATP-sensitive K+ channel activators, or smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier. The present invention also provides methods of using these compositions.
In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising a xcex2-adrenergic receptor agonist, preferably a xcex22- or xcex23-adrenergic receptor agonist, either alone or in combination with another agent selected from cAMP-hydrolyzing PDE inhibitors (e.g., a PDE IV inhibitor), nonspecific PDE inhibitors, xcex11-adrenergic antagonists, estrogens or estrogen-like compounds, L-type Ca2+ channel blockers, or ATP-sensitive K+ channel activators, and methods of using those compositions.
In yet another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising an ATP-sensitive K+ channel activator, either alone or in combination with another agent selected from cAMP-dependent protein kinase activators, xcex11-adrenergic antagonists, estrogens, L-type Ca2+ channel blockers, or smooth muscle relaxants, and methods of using those compositions.
In still another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising an xcex11-adrenergic antagonist, either alone or in combination with another agent selected from cAMP-hydrolyzing PDE inhibitors (preferably a PDE IV inhibitor) or smooth muscle relaxants, and methods of using those compositions.
In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising xcex22-adrenergic agonists, either alone or in combination with another agent. Methods for the use of these compositions are also provided. In one group of embodiments, the xcex22-adrenergic agonists are used alone. In a preferred embodiment, the xcex22-adrenergic agonists is combined with a phosphodiesterase inhibitor. In another embodiment, the xcex22-adrenergic agonists are combined with one or more other IAS relaxing agents.
In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising adenosine receptor antagonists, either alone or in combination with another agent. Methods for the use of these compositions are also provided. In one group of embodiments, adenosine receptor antagonists are used alone. In another group of embodiments, the adenosine receptor antagonists are combined with at least one other IAS relaxing agent.
In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising cyclic nucleotide-dependent protein kinase activators, either alone or in combination with another agent. Methods for the use of these compositions are also provided. In one group of embodiments, cGMP-dependent protein kinase activators are used alone. In another group of embodiments, nonspecific cyclic nucleotide-dependent protein kinase activators are used alone. In yet another group of embodiments, nonspecific cyclic nucleotide-dependent protein kinase activators are used in combination with smooth muscle relaxants. In still another group of embodiments, cAMP-dependent protein kinase activators are provided in combination with L-type Ca2+ channel blockers.
In yet another aspect, the present invention provides a composition for the treatment of anorectal disorders comprising a methylxanthine compound. In preferred embodiments, the compound is theophylline or dyphylline. In still another embodiment, the methylxanthine compound is used alone. In still another embodiment, the methylxanthine compound is combined with another IAS relaxing agent.
In yet another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising an estrogen or other estrogenic compound, either alone or in combination with another agent. Methods for the use of these compositions are also provided. In one group of embodiments, estrogenic compounds are used alone. In another group of embodiments, the estrogenic compounds are used in combination with a second agent selected from phosphodiesterase inhibitors, xcex2-adrenergic receptor agonists, xcex11-adrenergic antagonists, L-type Ca2+ channel blockers, ATP-sensitive K+ channel activators, or smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier. The present invention further provides methods of using these compositions.
Where the compounds discussed above act through mechanisms distinctly different from nitroglycerin, they can be used to complement nitroglycerin therapy, or as stand alone products.
As noted above, methods of treating anorectal disorders are also provided herein. The methods of the invention comprise administering to a subject a suitable formulation of one or more of the compositions above. In related methods, treatment is carried out by administration of two or more agents in sequence, either by the same route of administration or by different routes of administration.